SUBSTITUTED 8&#39;-PYRI(MI)DINYL-DIHYDROSPIRO-[CYCLOALKYLAMINE]-PYRIMIDO[1,2-a]PYRIMIDIN-6-ONE DERIVATIVES

ABSTRACT

The invention relates to a dihydrospiro-[cycloalkylamine]-pyrimidone derivative represented by formula (I) or a salt thereof:  
                 
wherein: 
         X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C 1-2  alkyl group and a hydrogen atom; Y represents a bond, a carbonyl group, a methylene group optionally substituted; R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, the ring being optionally substituted; R2 represents a benzene ring or a naphthalene ring; the rings being optionally substituted;    R3 represents a hydrogen atom, a C 1-6  alkyl group or a halogen atom;    R4 represents a hydrogen atom, a C 1-4  alkoxy carbonyl group, a C 1-5  alkyl group optionally substituted; o and m represent 1 to 2; n represents 0 to 3; p represents 0 to 2; and q represents 0 to 2. The invention relates also to a medicament comprising the said derivative or a salt thereof as an active ingredient which is used for preventive and/or therapeutic treatment of a neurodegenerative disease caused by abnormal activity of GSK3β, such as Alzheimer disease.

TECHNICAL FIELD

The present invention relates to compounds that are useful as an activeingredient of a medicament for preventive and/or therapeutic treatmentof neurodegenerative diseases caused by abnormal activity of GSK3β.

BACKGROUND ART

GSK3β (glycogen synthase kinase 3β) is a proline directed serine,threonine kinase that plays an important role in the control ofmetabolism, differentiation and survival. It was initially identified asan enzyme able to phosphorylate and hence inhibit glycogen synthase. Itwas later recognized that GSK3β was identical to tau protein kinase 1(TPK1), an enzyme that phosphorylates tau protein in epitopes that arealso found to be hyperphosphorylated in Alzheimer's disease and inseveral taupathies. Interestingly, protein kinase B (AKT)phosphorylation of GSK3β results in a loss of its kinase activity, andit has been hypothesized that this inhibition may mediate some of theeffects of neurotrophic factors. Moreover, phosphorylation by GSK3β ofβ-catenin, a protein involved in cell survival, results in itsdegradation by an ubiquitinilation dependent proteasome pathway.

Thus, it appears that inhibition of GSK3β activity may result inneurotrophic activity. Indeed there is evidence that lithium, anuncompetitive inhibitor of GSK3β, enhances neuritogenesis in some modelsand also increases neuronal survival, through the induction of survivalfactors such as Bcl-2 and the inhibition of the expression ofproapoptotic factors such as P53 and Bax.

Recent studies have demonstrated that β-amyloid increases the GSK3βactivity and tau protein phosphorylation. Moreover, thishyperphosphorylation as well as the neurotoxic effects of β-amyloid areblocked by lithium chloride and by a GSK3β antisense mRNA. Theseobservations strongly suggest that GSK3β may be the link between the twomajor pathological processes in Alzheimer's disease: abnormal APP(Amyloid Precursor Protein) processing and tau proteinhyperphosphorylation.

Although tau hyperphosphorylation results in a destabilization of theneuronal cytoskeleton, the pathological consequences of abnormal GSK3βactivity are, most likely, not only due to a pathologicalphosphorylation of tau protein because, as mentioned above, an excessiveactivity of this kinase may affect survival through the modulation ofthe expression of apoptotic and antiapoptotic factors. Moreover, it hasbeen shown that β-amyloid-induced increase in GSK3β activity results inthe phosphorylation and, hence the inhibition of pyruvate dehydrogenase,a pivotal enzyme in energy production and acetylcholine synthesis.

Altogether these experimental observations indicate that GSK3β may findapplication in the treatment of the neuropathological consequences andthe cognitive and attention deficits associated with Alzheimer'sdisease, as well as other acute and chronic neurodegenerative diseases.These include, in a non-limiting manner, Parkinson's disease,tauopathies (e.g. frontotemporoparietal dementia, corticobasaldegeneration, Pick's disease, progressive supranuclear palsy) and otherdementia including vascular dementia; acute stroke and others traumaticinjuries; cerebrovascular accidents (e.g. age related maculardegeneration); brain and spinal cord trauma; peripheral neuropathies;retinopathies and glaucoma.

In addition GSK3β may find application in the treatment of otherdiseases such as: Non-insulin dependent diabetes (such as diabetes typeII) and obesity; manic depressive illness; schizophrenia; alopecia;cancers such as breast cancer, non-small cell lung carcinoma, thyroidcancer, T or B-cell leukemia and several virus-induced tumors.

DISCLOSURE OF THE INVENTION

An object of the present invention is to provide compounds useful as anactive ingredient of a medicament for preventive and/or therapeutictreatment of a disease caused by abnormal GSK3β activity, moreparticularly of neurodegenerative diseases. More specifically, theobject is to provide novel compounds useful as an active ingredient of amedicament that enables prevention and/or treatment of neurodegenerativediseases such as Alzheimer's disease.

Thus, the inventors of the present invention have identified compoundspossessing inhibitory activity against GSK3β. As a result, they foundthat compounds represented by the following formula (I) had the desiredactivity and were useful as an active ingredient of a medicament forpreventive and/or therapeutic treatment of the aforementioned diseases.

The present invention thus providesdihydrospiro-[cycloalkylamine]-pyrimidone derivatives represented byformula (I) or salts thereof, solvates thereof or hydrates thereof:

wherein:

X represents two hydrogen atoms, a sulfur atom, an oxygen atom or a C₁₋₂alkyl group and a hydrogen atom;

Y represents a bond, a carbonyl group, a methylene group optionallysubstituted by one or two groups chosen from a C₁₋₆ alkyl group, ahydroxyl group, a C₁₋₄ alkoxy group, a C₁₋₂ perhalogenated alkyl groupor an amino group;

R1 represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring,the ring being optionally substituted by a C₁₋₄ alkyl group, a C₁₋₄alkoxy group, or a halogen atom;

R2 represents a benzene ring or a naphthalene ring; the rings beingoptionally substituted by 1 to 4 substituents selected from a C₁₋₆ alkylgroup, a methylendioxy group, a halogen atom, a C₁₋₂ perhalogenatedalkyl group, a C₁₋₃ halogenated alkyl group, a hydroxyl group, a C₁₋₄alkoxy group, a nitro, a cyano, an amino, a C₁₋₅ monoalkylamino group ora C₂₋₁₀ dialkylamino group;

R3 represents a hydrogen atom, a C₁₋₆ alkyl group or a halogen atom;

R4 represents a hydrogen atom, a C₁₋₄ alkoxy carbonyl group, a C₁₋₆alkyl group optionally substituted by 1 to 4 substituents selected froma halogen atom, a hydroxyl group or a C₁₋₄ alkoxy group;

o and m represent 1 to 2;

n represents 0 to 3;

p represents 0 to 2; and

q represents 0 to 2.

According to another aspect of the present invention, there is provideda medicament comprising as an active ingredient a substance selectedfrom the group consisting of the pyrimidone derivatives represented byformula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof. As preferred embodiments ofthe medicament, there are provided the aforementioned medicament whichis used for preventive and/or therapeutic treatment of diseases causedby abnormal GSK3β activity, and the aforementioned medicament which isused for preventive and/or therapeutic treatment of neurodegenerativediseases and in addition other diseases such as: Non-insulin dependentdiabetes (such as diabetes type II) and obesity; manic depressiveillness; schizophrenia; alopecia; cancers such as breast cancer,non-small cell lung carcinoma, thyroid cancer, T or B-cell leukemia andseveral virus-induced tumors.

As further preferred embodiments of the present invention, there areprovided the aforementioned medicament wherein the diseases areneurodegenerative diseases and are selected from the group consisting ofAlzheimer's disease, Parkinson's disease, tauopathies (e.g.frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma, and the aforementioned medicament in the form ofpharmaceutical composition containing the above substance as an activeingredient together with one or more pharmaceutical additives.

The present invention further provides an inhibitor of GSK3β activitycomprising as an active ingredient a substance selected from the groupconsisting of the dihydrospiro-[cycloalkylamine]-pyrimidone derivativesof formula (I) and the salts thereof, and the solvates thereof and thehydrates thereof.

According to further aspects of the present invention, there is provideda method for preventive and/or therapeutic treatment ofneurodegenerative diseases caused by abnormal GSK3β activity, whichcomprises the step of administering to a patient a preventively and/ortherapeutically effective amount of a substance selected from the groupconsisting of dihydrospiro-[cycloalkylamine]-pyrimidone derivatives offormula (I) and the physiologically acceptable salts thereof, and thesolvates thereof and the hydrates thereof; and a use of a substanceselected from the group consisting of thedihydrospiro-[cycloalkylamine]-pyrimidone derivatives of formula (I) andthe physiologically acceptable salts thereof, and the solvates thereofand the hydrates thereof for the manufacture of the aforementionedmedicament.

As used herein, the C₁₋₆ alkyl group represents a straight or branchedalkyl group having 1 to 6 carbon atoms, for example, methyl group, ethylgroup, n-propyl group, isopropyl group, n-butyl group, isobutyl group,sec-butyl group, tert-butyl group, n-pentyl group, isopentyl group,neopentyl group, 1,1-dimethylpropyl group, n-hexyl group, isohexylgroup, and the like;

The C₁₋₄ alkoxy group represents an alkyloxy group having 1 to 4 carbonatoms for example, methoxy group, ethoxy group, propoxy group,isopropoxy group, butoxy group, isobutoxy group, sec-butoxy group,tert-butoxy group, and the like;

The halogen atom represents a fluorine, chlorine, bromine or iodineatom;

The C₁₋₂ perhalogenated alkyl group represents an alkyl group whereinall the hydrogen have been substituted by a halogeno, for example a CF₃or C₂F₅;

The C₁₋₃ halogenated alkyl group represents an alkyl group wherein atleast one hydrogen has not been substituted by an halogen atom;

The C₁₋₅ monoalkylamino group represents an amino group substituted byone C₁₋₆ alkyl group, for example, methylamino group, ethylamino group,propylamino group, isopropylamino group, butylamino group, isobutylaminogroup, tert-butylamino group, pentylamino group and isopentylaminogroup;

The C₂₋₁₀ dialkylamino group represents an amino group substituted bytwo C₁₋₅ alkyl groups, for example, dimethylamino group,ethylmethylamino group, diethylamino group, methylpropylamino group anddiisopropylamino group;

A leaving group L represents a group which could be easily cleaved andsubstituted, such a group may be for example a tosyl, a mesyl, a bromideand the like.

The compounds represented by the aforementioned formula (I) may form asalt, Examples of the salt include, when an acidic group exists, saltsof alkali metals and alkaline earth metals such as lithium, sodium,potassium, magnesium, and calcium; salts of ammonia and amines such asmethylamine, dimethylamine, trimethylamine, dicyclohexylamine,tris(hydroxymethyl)aminomethane, N,N-bis(hydroxyethyl)piperazine,2-amino-2-methyl-1-propanol, ethanolamine, N-methylglucamine, andL-glucamine; or salts with basic amino acids such as lysine,δ-hydroxylysine, and arginine. The base-addition salts of acidiccompounds are prepared by standard procedures well known in the art.

When a basic group exists, examples include salts with mineral acidssuch as hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid,phosphoric acid; salts with organic acids such as methanesulfonic acid,benzenesulfonic acid, p-toluenesulfonic acid, acetic acid, propionicacid, tartaric acid, fumaric acid, maleic acid, malic acid, oxalic acid,succinic acid, citric acid, benzoic acid, mandelic acid, cinnamic acid,lactic acid, glycolic acid, glucuronic acid, ascorbic acid, nicotinicacid, and salicylic acid; or salts with acidic amino acids such asaspartic acid, and glutamic acid.

The acid-addition salts of the basic compounds are prepared by standardprocedures well know in the art which include, but are not limitedthereto, dissolving the free base in an aqueous alcohol solutioncontaining the appropriate acid and isolating the salt by evaporatingthe solution, or by reacting the free base and an acid in an organicsolvent, in which case the salt separates directly, or is precipitatedwith a second organic solvent, or can be obtained by concentration ofthe solution. The acids which can be used to prepare the acid-additionsalts include preferably those which produce, when combined with thefree base, pharmaceutically-acceptable salts, that is, salts whoseanions are relatively innocuous to the animal organism in pharmaceuticaldoses of the salts, so that the beneficial properties inherent in thefree base are not compromised by side effects ascribable to the anions.Although medicinally acceptable salts of the basic compounds arepreferred, all acid-addition salts are within the scope of the presentinvention.

In addition to the dihydrospiro-[cycloalkylamine]-pyrimidone derivativesrepresented by the aforementioned formula (I) and salts thereof, theirsolvates and hydrates also fall within the scope of the presentinvention.

The dihydrospiro-[cycloalkylamine]-pyrimidone derivatives represented bythe aforementioned formula (I) may have one or more asymmetric carbonatoms. As for the stereochemistry of such asymmetric carbon atoms, theymay independently be in either (R) and (S) configuration, and thederivative may exist as stereoisomers such as optical isomers, ordiastereoisomers. Any stereoisomers in pure form, any mixtures ofstereoisomers, racemates and the like fall within the scope of thepresent invention.

Examples of preferred compounds of the present invention are shown intable 1 hereinafter. However, the scope of the present invention is notlimited by these compounds.

Preferred compounds of the present invention represented by formula (I)include also compounds wherein:

(1) Ri represents a 3- or 4-pyridine ring and more preferably 4-pyridinering or a 4- or 5-pyrimidine ring and more preferably 4-pyrimidine ring,which may be substituted by a C₁₋₂ alkyl group, a C₁₋₂ alkoxy group or ahalogen atom; and/or

(2) R2 represents a benzene ring or a naphthalene ring, the ring beingoptionally substituted 1 to 4 substituents selected from a C₁₋₃ alkylgroup, a halogen atom, a hydroxyl group or a C₁₋₂ alkoxy group; and/or

(3) R3 represents a hydrogen atom, a C₁₋₃ alkyl group or a halogen atom;more preferably a hydrogen atom; and/or

(4) R4 represents a hydrogen atom, a C₁₋₄ alkoxy carbonyl group, a C₁₋₃alkyl group optionally substituted by 1 to 4 substituents selected froma halogen atom, a hydroxyl group or a C₁₋₄ alkoxy group; and/or

(5) Y represents a carbonyl group or methylene group optionallysubstituted by one or two groups chosen from a C₁₋₃ alkyl group, ahydroxyl group, a C₁₋₄ alkoxy group, a C₁₋₂ perhalogenated alkyl group,an amino group; and more particularly wherein R1, R2, R3, R4 and Y areas defined here-above.

More preferred compounds of the present invention represented by formula(I) include also compounds wherein:

(1) RI represents an unsubstituted 4-pyridine ring or 4-pyrimidine ring;and/or

(2) R2 represents a benzene ring, the ring being optionally substituted1 to 4 substituents selected from a C₁₋₃ alkyl group, a halogen atom, ahydroxyl group or a C₁₋₂ alkoxy group; and/or

(3) R3 represents a hydrogen atom; and/or

(4) R4 represents a C₁₋₄ alkoxy carbonyl group or a C₁₋₃ alkyl groupoptionally substituted by 1 to 4 substituents selected from a halogenatom or a hydroxyl group; and/or

(5) X represents two hydrogen atoms; and/or

(6) Y represents a carbonyl group or a methylene group optionallysubstituted by a hydroxyl group; and/or

(7) p represents 2 and q represents 0; and more particularly wherein R1,R2, R3, X, Y, p, q, m, o and n are as defined here-above.

Particularly preferred compounds of the present invention represented byformula (I), wherein R1 is a pyridine ring or a pyrimidine ring, includecompounds of table 1:

1.Ethyl-1′-[(2S)-2-hydroxy-2-phenylethyl]-6′-oxo-8′-(pyridin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate

2.Ethyl-6′-oxo-1′-[2-oxo-2-phenylethyl]-8′-(pyridin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate

3.1′-[(2S)-2-Hydroxy-2-phenylethyl]-1-methyl-8′-(pyridin-4-yl)-3′,4′-dihydrospiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one

4.1-Methyl-1′-(2-oxo-2-phenylethyl)-8′-(pyridin-4-yl)-3′,4′-dihydrospiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one

5.Ethyl-1′-[(2S)-2-hydroxy-2-phenylethyl]-6′-oxo-8′-(pyrimidin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate

6.Ethyl-6′-oxo-1′-[2-oxo-2-phenylethyl]-8′-(pyrimidin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate

7.1′-[(2S)-2-Hydroxy-2-phenylethyl]-1-methyl-8′-(pyrimidin-4-yl)-3′,4′-dihydrospiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one;

and compounds of table 2:

1. Ethyl1-[(2S)-2-hydroxy-2-phenylethyl]6-oxo-8-(pyridin-4-yl)-1,3,4,6-tetrahydro-1′H-spiro[pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidine]-1′-carboxylate

2. Ethyl6-oxo-1-(2-oxo-2-phenylethyl)-8-(pyridin-4-yl)-1,3,4,6-tetrahydro-1′H-spiro[pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidine]-1′-carboxylate

3.1-[(2S)-2-hydroxy-2-phenylethyl]-1′-methyl-8-(pyridin-4-yl)-3,4-dihydrospiro[pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1H)-one

4.1′-Methyl-1-(2-oxo-2-phenylethyl)-8-(pyridin-4-yl)-3,4-dihydrospiro(pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1H)-one.

As a further object, the present invention concerns also methods forpreparing the dihydrospiro-[cycloalkylamine]-pyrimidone compoundsrepresented by the aforementioned formula (I).

These compounds can be prepared, for example, according to methodsexplained below.

Preparation Method

Dihydrospiro-[cycloalkylamine]-pyrimidone compounds represented by theaforementioned formula (I), may be prepared according to the methoddescribed in the scheme 1.

(In the above scheme the definition of R1, R2, R3, R4, X, Y, m, n, o, pand q are the same as those already described for compound of formula(I)).

Following this method, the pyrimidinone derivative represented by theabove formula (III), wherein R1, R3, R4, m, n, o, p and q are as definedfor compound of formula (I), is allowed to react with a base such assodium hydride, sodium carbonate or potassium carbonate in a solventsuch as N,N-dimethylformamide, N-methylpyrrolidone,N,N-dimethylacetamide or chloroform at a suitable temperature rangingfrom 0 to 130° C. under ordinary air, then with a compound of formula(II), wherein R2, X, Y and n are as defined for compound of formula (I)and L represents a leaving group preferably bromide or mesyl group, toobtain the compound of the aforementioned formula (I).

Alternatively compounds of formula (I) wherein Y represents a carbonylgroup may be prepared by oxydation of a compound of formula (I) whereinY represents a methylene group substituted by a hydroxyl group accordingto well known methods to one skilled in the art.

Compound of formula (II) is commercially available or may be synthesizedaccording to well-known methods to one skilled in the art.

Compound of formula (III) may be prepared according to the methoddefined in scheme 2.

(In the above scheme the definition of R1, R3,R4, m, o, p and q are thesame as already described.)

According to this method, the 3-ketoester of formula (IV), wherein R1and R3 are as defined for compound of formula (I) and R is an alkylgroup such as for example methyl or ethyl, is allowed to react with acompound of formula (V). The reaction may be carried out in the presenceof a base such as potassium carbonate, in an alcoholic solvent such asmethanol, ethanol and the like or without, at a suitable temperatureranging from 25° to 140° C. under ordinary air.

Alternatively, compound of formula (III) wherein R3 represents ahydrogen atom may be halogenated in order to give compounds of formula(III) wherein R3 is a halogen atom such as a bromine atom or a chlorineatom. The reaction may be carried out in an acidic medium such as aceticacid or propionic acid, in presence of bromosuccinimide orchlorosuccimide, or bromine.

In addition, compounds of formula (III) wherein R3 represents a fluorineatom may be obtained by analogy to the method described in TetrahedronLetters, Vol. 30, N°45, pp 6113-6116, 1989.

Compound of formula (IV) is commercially available or may be synthesizedaccording to well-known methods to one skilled in the art.

For example compounds of formula (IV), wherein R1 represent a pyridinering or a pyrimidine ring, optionally substituted by a C₁₋₄ alkyl group,C₁₋₄ alkoxy group or a halogen atom, can be prepared by reactingrespectively an isonicotinic acid or a pyrimidine-carboxylic acid,optionally substituted by a C₁₋₄ alkyl group, C₁₋₄ alkoxy group or ahalogen, with the corresponding malonic acid monoester. The reaction canbe carried out using methods well known to one skilled in the art, suchas for example in presence of a coupling agent such as1,1′-carbonylbis-1H-imidazole in a solvent such as tetrahydrofuran at atemperature ranging from 20 to 70° C.

Compound of formula (V) may be synthesized according to well-knownmethods of one skilled in the art.

For example compound of formula (V), when m and o represent 2, prepresents 2 and q represents 0, may be prepared according to the methoddefined in scheme 3 and starting from compound (VI), wherein R4 is asdefined for formula (I) The conditions which may be used are given inthe chemical examples.

(In the above scheme Pg represents an amino-protecting group and L aleaving group)

Compound of formula (VI) may be synthesized according to the methoddescribed in J. Med. Chem. 1991, 34, 90-97.

Compound of formula (VII) may be synthesized according to the methoddescribed in Synthetic Communication 28(4), 701-712 (1998).

As a further object, the present invention concerns also the compoundsof formula (III) as intermediates of compounds of formula (I).

In the above reactions protection or deprotection of a functional groupmay sometimes be necessary. A suitable protecting group Pg can be chosendepending on the type of the functional group, and a method described inthe literature may be applied. Examples of protecting group, ofprotection and deprotection methods are given for example in Protectivegroups in Organic Synthesis Greene et al., 2nd Ed. (John Wiley & Sons,Inc., New York).

The compounds of the present invention have inhibitory activity againstGSK3β. Accordingly, the compounds of the present invention are useful asan active ingredient for the preparation of a medicament, which enablespreventive and/or therapeutic treatment of a disease caused by abnormalGSK3β activity and more particularly of neurodegenerative diseases suchas Alzheimer's disease. In addition, the compounds of the presentinvention are also useful as an active ingredient for the preparation ofa medicament for preventive and/or therapeutic treatment ofneurodegenerative diseases such as Parkinson's disease, tauopathies(e.g. frontotemporoparietal dementia, corticobasal degeneration, Pick'sdisease, progressive supranuclear palsy) and other dementia includingvascular dementia; acute stroke and others traumatic injuries;cerebrovascular accidents (e.g. age related macular degeneration); brainand spinal cord trauma; peripheral neuropathies; retinopathies andglaucoma; and other diseases such as non-insulin dependent diabetes(such as diabetes type II) and obesity; manic depressive illness;schizophrenia; alopecia; cancers such as breast cancer, non-small celllung carcinoma, thyroid cancer, T or B-cell leukemia and severalvirus-induced tumors.

The present invention further relates to a method for treatingneurodegenerative diseases caused by abnormal activity of GSK3β and ofthe aforementioned diseases which comprises administering to a mammalianorganism in need thereof an effective amount of a compound of theformula (I).

As the active ingredient of the medicament of the present invention, asubstance may be used which is selected from the group consisting of thecompound represented by the aforementioned formula (I) andpharmacologically acceptable salts thereof, and solvates thereof andhydrates thereof. The substance, per se, may be administered as themedicament of the present invention, however, it is desirable toadminister the medicament in a form of a pharmaceutical compositionwhich comprises the aforementioned substance as an active ingredient andone or more pharmaceutical additives. As the active ingredient of themedicament of the present invention, two or more of the aforementionedsubstances may be used in combination. The above pharmaceuticalcomposition may be supplemented with an active ingredient of anothermedicament for the treatment of the above mentioned diseases. The typeof pharmaceutical composition is not particularly limited, and thecomposition may be provided as any formulation for oral or parenteraladministration. For example, the pharmaceutical composition may beformulated, for example, in the form of pharmaceutical compositions fororal administration such as granules, fine granules, powders, hardcapsules, soft capsules, syrups, emulsions, suspensions, solutions andthe like, or in the form of pharmaceutical compositions for parenteraladministrations such as injections for intravenous, intramuscular, orsubcutaneous administration, drip infusions, transdermal preparations,transmucosal preparations, nasal drops, inhalants, suppositories and thelike. Injections or drip infusions may be prepared as powderypreparations such as in the form of lyophilized preparations, and may beused by dissolving just before use in an appropriate aqueous medium suchas physiological saline. Sustained-release preparations such as thosecoated with a polymer may be directly administered intracerebrally.

Types of pharmaceutical additives used for the manufacture of thepharmaceutical composition, content ratios of the pharmaceuticaladditives relative to the active ingredient, and methods for preparingthe pharmaceutical composition may be appropriately chosen by thoseskilled in the art. Inorganic or organic substances, or solid or liquidsubstances may be used as pharmaceutical additives. Generally, thepharmaceutical additives may be incorporated in a ratio ranging from 1%by weight to 90% by weight based on the weight of an active ingredient.

Examples of excipients used for the preparation of solid pharmaceuticalcompositions include, for example, lactose, sucrose, starch, talc,cellulose, dextrin, kaolin, calcium carbonate and the like. For thepreparation of liquid compositions for oral administration, aconventional inert diluent such as water or a vegetable oil may be used.The liquid composition may contain, in addition to the inert diluent,auxiliaries such as moistening agents, suspension aids, sweeteners,aromatics, colorants, and preservatives. The liquid composition may befilled in capsules made of an absorbable material such as gelatin.Examples of solvents or suspension mediums used for the preparation ofcompositions for parenteral administration, e.g. injections,suppositories, include water, propylene glycol, polyethylene glycol,benzyl alcohol, ethyl oleate, lecithin and the like. Examples of basematerials used for suppositories include, for example, cacao butter,emulsified cacao butter, lauric lipid, witepsol.

The dose and frequency of administration of the medicament of thepresent invention are not particularly limited, and they may beappropriately chosen depending on conditions such as a purpose ofpreventive and/or therapeutic treatment, a type of a disease, the bodyweight or age of a patient, severity of a disease and the like.Generally, a daily dose for oral administration to an adult may be 0.01to 1,000 mg (the weight of an active ingredient), and the dose may beadministered once a day or several times a day as divided portions, oronce in several days. When the medicament is used as an injection,administrations may preferably be performed continuously orintermittently in a daily dose of 0.001 to 100 mg (the weight of anactive ingredient) to an adult.

CHEMICAL EXAMPLES Example 1 Compound N° 1 of Table 1

Ethyl-1′-[(2S)-2-hydroxy-2-phenylethyl]-6′-oxo-8′-(pyridin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate.(1:1) (Hydrochloride)

1.1 4-Cyanomethylene-piperidine-1-carboxylic Acid Ethyl Ester

To a suspension of 12.85 g (321.28 mmol) of sodium hydride (60%suspension in mineral oil) in 500 ml of anhydrous tetrahydrofuran at 0°C., was added 56.91 g (321.28 mmol) of diethyl-(cyanomethyl)-phosphonateover a 10-min period. The reaction mixture was stirred for 2 h at roomtemperature and then 44.05 g (292.07 mmol) of4-oxo-piperidine-1-carboxylic acid ethyl ester in 230 ml of anhydroustetrahydrofuran was added dropwise over 30 min. The resulting mixturewas stirred at room temperature for 16 h.

The mixture was dissolved in 1 l of diethyl ether and washed with asaturated aqueous solution of ammonium chloride, saturated aqueoussodium chloride, dried over sodium sulfate and evaporated. The crudeproduct was triturated with petroleum ether and filtered to afford 51.63g of pure product as a yellow solid.

Mp: 95-96° C.

1.2 4-Amino-4-cyanomethyl-piperidine-1-carboxylic Acid Ethyl Ester

A solution of 51.38 g (264.53 mol) of4-cyanomethylene-piperidine-1-carboxylic acid ethyl ester in 301 ml ofan aqueous ammonia solution (29%) and 50 ml of methanol was heated at110° C. in a sealed tube for 48 h. The reaction mixture wasconcentrated, and the residue was chromatographed on silica gel elutingwith a mixture of dichloromethane/methanol in the proportions 100/0 to96/4 to afford 40 g of the product as a white solid.

Mp: 68-69° C.

1.3 4-tert-Butoxycarbonylamino-4-cyanomethyl-piperidine-1-carboxylicAcid Ethyl Ester

To a solution of 35.44 g (167.79 mmol) of4-amino-4-cyanomethyl-piperidine-1-carboxylic acid ethyl ester in 200 mlof tetrahydrofuran was added 4.3 ml of water, 23.58 ml (167.79 mmol) oftriethylamine and 36.61 g (167.79 mmol) of di-tert-butyl dicarbonate in50 ml of tetrahydrofuran. The resulting mixture was stirred at roomtemperature for 16 h.

The mixture was dissolved in dichloromethane and washed with a saturatedaqueous solution of ammonium chloride, saturated aqueous sodiumchloride, dried over sodium sulfate and evaporated. The crude productwas triturated with pentane and filtered to afford 46.49 g of pureproduct as a white solid.

Mp: 133-135° C.

1.4 4-(2-Amino-ethyl)-4-tert-butoxycarbonylamino-piperidine-1-carboxylicAcid Ethyl Ester

To a solution of 5 g (16.06 mmol) of4-tert-butoxycarbonylamino-4-cyanomethyl-piperidine-1-carboxylic acidethyl ester in 107 ml of methanol was added 4.71 g of Raney Nickelcatalyst. The suspension was hydrogenated under 55 psi pressure at roomtemperature during 3 h.

The catalyst was removed by filtration and the solvent evaporated underreduced pressure. Purification by chromatography on silica gel elutingwith a mixture of dichloromethane/methanol/aqueous ammonia solution(29%) in the proportions 100/0/0 to 70/30/3 led to compound in the formof an oil (2.86 g).

1.5 4-Amino-4-(2-amino-ethyl)-piperidine-1-carboxylic Acid Ethyl EsterHydrochloride (2:1)

To a solution of 3.01 g (9.56 mmol) of4-(2-amino-ethyl)-4-tert-butoxycarbonylamino-piperidine-1-carboxylicacid ethyl ester in 19 ml of isopropanol was added 8 ml of a solution ofhydrochloric acid (5.6 N) in isopropanol and the resulting solution wasstirred at room temperature for 3 h. The mixture was cooled and diethylether was added. The resulting precipitate was filtered. The product wasdried to give 2.49 g of pure compound as a white solid.

Mp: 119-121° C.

1.6 2-Amino-1,3,9-triaza-spiro[5.5]undec-2-ene-9-carboxylic Acid EthylEster Hydrobromide (1:1)

To a solution of 15.65 g (54.33 mmol) of4-amino-4-(2-amino-ethyl)-piperidine-1-carboxylic acid ethyl esterhydrochloride (2:1) in 108 ml of methanol was added 21.73 ml (114.09mmol) of a solution of sodium methoxide in methanol (5.55 N). Themixture was stirred at room temperature for 2 h. The precipitate wasfiltered and the filtrate was evaporated. The crude was dissolved in 108ml of water and 5.75 g (54.33 mmol) of cyanogen bromide was addedportion wise. The resulting mixture was stirred at room temperature for16 h, evaporated to dryness, dissolved in ethanol and evaporated todryness to give 17.56 g of pure compound as a brown solid.

1.7 Ethyl 6′-oxo-8′-(pyridin4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate

A mixture of 3 g (15.57 mmol) of ethyl 3-(pyridin-4-yl)-3-oxopropionate,5 g (15.57 mmol) of2-amino-1,3,9-triaza-spiro[5.5]undec-2-ene-9-carboxylic acid ethyl esterhydrobromide (1:1) and 4.52 g (32.70 mmol) of potassium carbonate in 28ml of ethanol was heated at reflux temperature during 12 h.

The cooled solution was evaporated to removed solvent. The mixture wasdissolved in dichloromethane and washed with a saturated aqueoussolution of ammonium chloride, dried over sodium sulfate and evaporated.The residue was treated with water and the precipitate was filtered, thecrude product was triturated with diethyl ether and filtered to afford2.94 g of pure product as a white solid.

Mp: 209-210° C.

1.8Ethyl-1′-[(2S)-2-hydroxy-2-phenylethyl]-6′-oxo-8′-(pyridin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate.(1:1) (Hydrochloride)

To a solution of 0.6 g (1.62 mmol) of ethyl6′-oxo-8′-(pyridin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylatein 13 ml of anhydrous dimethylformamide was added 0.085 g (2.11 mmol) ofsodium hydride (60% suspension in mineral oil). The mixture was allowedto stir at 50° C. for 1 h. Then 0.25 g (2.11 mmol) of (S)-phenyloxiranewas added and the mixture allowed to stir at 110° C. for 12 h.

0.25 g (2.11 mmol) of (S)-phenyloxirane was added and the mixtureallowed to stir at 110° C. for 6 h. Water was added and the mixtureextracted with dichloromethane. The extracts were washed with asaturated aqueous solution of sodium chloride, dried and evaporated togive crude product. Purification by chromatography on silica gel elutingwith a mixture of ethyl dichloromethane/methanol in the proportions100/0 to 90/10 led to compound in the form of free base. The base wastransformed into its hydrochloride salt to give 0.144 g of pure product.

Mp: 169-170° C., [α]_(D)=−13.7° (c=0.99, dimethylsulfoxide).

RMN ¹H (DMSO-d⁶; 200 MHz)

δ (ppm): 8.95 (brd, 2H); 8.35 (d, 2H); 7.12-7.42 (m, 5H); 6.66 (s, 1H);5.02 (m, 1H); 4.00 (q, 2H); 3.52-3.95 (m, 6H); 2.78-3.11 (m, 2H);1.95-2.4 (m, 4H); 1.65-1.90 (m, 2H); 71.15 (t, 3H).

Example 2 (Compound N° 2 of Table 1

Ethyl-6′-oxo-1′-[2-oxo-2-phenylethyl]-8′-(pyridin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate.(1:1) (Hydrochloride)

0.138 g (0.28 mmol) ofethyl-1′-[(2S)-2-hydroxy-2-phenylethyl]-6′-oxo-8′-(pyridin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylatewas dissolved in 2.82 ml of anhydrous dichloromethane and mixed with0.049 g (0.42 mmol) of N-methylmorpholine N-oxide, 0.001 g (0.0083 mmol)of tetra-n-propylammonium perruthenate and 1 g of powdered molecularsieves (4A). The mixture was stirred at 20° C. under nitrogen atmospherefor 12 h.

0.049 g (0.42 mmol) of N-methylmorpholine N-oxide, 0.001 g (0.0014 mmol)of tetra-n-propylammonium perruthenate and 1 g of powdered molecularsieves (4A) were added and the mixture was stirred at 20° C. undernitrogen atmosphere for 3 h. Purification of the crude by chromatographyon silica gel eluting with a mixture of dichloromethane/methanol in theproportions 100/0 to 95/5 gave the compound in the form of free basewhich was transformed into its hydrochloride salt to give 0.045 g ofpure product.

Mp: 227-229° C.

RMN ¹H (DMSO-d⁶; 200 MHz)

δ (ppm) : 8.46 (br d, 2H); 8.05 (d, 2H); 7.51-782 (m, 5H); 6.63 (s, 1H);5.22 (s, 2H); 3.85-4.08 (m, 6H); 2.89-3.25 (m, 2H); 2.21-2.37 (m, 2H);1.95 (td, 2H); 1.66 (d, 2H); 1.15 (t, 3H).

Example 3 (Compound N° 3 of Table 1

1′-[(2S)-2-Hydroxy-2-phenylethyl]-1-methyl-8′-(pyridin-4-yl)-3′,4′-dihydrospiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one.(2:1) (Hydrochloride)

3.11-Methyl-8′-(pyridin-4-yl)-3′,4′-dihydrospiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one

To a solution of 0.6 g (1.62 mmol) of ethyl6′-oxo-8′-(pyridin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylatedissolved in 3.25 ml of tetrahydrofuran at 0° C. was added 0.185 g (4.87mmol) of lithium aluminium hydride. The resulting mixture was stirred atroom temperature under nitrogen atmosphere for 3 h.

The reaction mixture was treated with excess of a saturated aqueoussolution of sodium sulfate. Further solid sodium sulfate was added andthe organic phase was filtered to remove salts. The solvent wasevaporated and purification by chromatography on silica gel eluting witha mixture of dichloromethane/methanol in the proportions 100/0 to 70/30led to compound in the form of a yellow solid (0.328 g).

Mp: 232-234° C.

3.21′-[(2S)-2-Hydroxy-2-phenylethyl]-1-methyl-8′-(pyridin-4-yl)-3′,4′-dihydrospiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one.(2:1) (Hydrochloride)

The product was obtained by analogy with the method described in step1.9 and using1-methyl-8′-(pyridin-4-yl)-3′,4′-dihydrospiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one.

Mp: 271-272° C., [α]_(D)=−10.2° (c=0.829, CH₃OH).

RMN ¹H (DMSO-d⁶; 200 MHz)

δ (ppm): 10.75 (br s, 1H); 8.91 (d, 2H); 8.31 (d, 2H); 7.20-759 (m, 5H);6.71 (s, 1H); 5.12 (m, 1H); 3.58-4.50 (m, 4H) ; 3.00-3.45 (m, 4H); 2.85(m, 1H); 2.75 (s, 3H) 2.08-2.44 (m, 3H) ; 1.89 (br d, 1H); 1.45 (br d,1H).

Example 4 (Compound N° 5 of Table 1

Ethyl-1′-[(2S)-2-hydroxy-2-phenylethyl]-6′-oxo-8′-(pyrimidin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate

4.1 Ethyl6′-oxo-8′-(pyrimidinyl-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate

The product was obtained by analogy with the method described in example1 (step 1.7) and using 3-oxo-3-pyrimidin-4-yl-propionic acid methylester.

Mp: 231-233° C.

4.2Ethyl-1′-[(2S)-2-hydroxy-2-phenylethyl]-6′-oxo-8′-(pyrimidin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate

The product was obtained by analogy with the method described in step1.8 and using ethyl6′-oxo-8′-(pyrimidinyl-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate.

Mp: 118-120° C., [α]_(D)=−13.2° (c=1.028, CH₃OH).

RMN ¹H (DMSO-d⁶; 200 MHz) δ (ppm): 9.27 (s, 1H); 8.98 (d, 1H) ; 8.10 (d,1H); 7.15-7.43 (m, 5H); 6.70 (s, 1H); 5.48 (d, 1H); 5.05 (m, 1H); 4.04(q, 2H); 3.52-4.10 (m, 5H); 2.92 (brq, 2H);

1.90-2.39 (m, 3H); 1.63-1.90 (m, 3H); 1.15 (t, 3H).

Example 5 (Compound N° 7 of Table 1

1′-[(2S)-2-Hydroxy-2-phenylethyl]-1-methyl-8′-(pyrimidin-4-yl)-3′,4′-dihydrospiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one

5.11-Methyl-8′-(pyrimidin-4-yl)-3′,4′-dihydrospiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one

The product was obtained by analogy with the method described in example3 (step 3.1) and using 3-oxo-3-pyrimidin-4-yl-propionic acid methylester.

Mp: 194-196° C.

5.21′-[(2S)-2-Hydroxy-2-phenylethyl]-1-methyl-8′-(pyrimidin-4-yl)-3′,4′-dihydrospiro[piperidine4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one

The product was obtained by analogy with the method described in step1.8 and using1-methyl-8′-(pyrimidin-4-yl)-3′,4′-dihydrospiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one.

Mp: 180-182° C.

RMN ¹H (DMSO-d⁶; 200 MHz)

δ (ppm): 9.35 (s, 1H); 9.05 (d, 1H); 8.17 (d, 1H); 7.25-7.45 (m, 5H);6.75 (s, 1H); 5.57 (d, 1H); 5.10 (m, 1H); 3.67-4.05 (m, 4H); 2.67 (brdd,2H); 2.22 (s, 3H); 1.82-2.35 (m, 5H); 1.67 (br d, 1H); 1.20 (m, 1H).

Example 6 3-cyanomethylene-pyrrolidine-1-carboxylic Acid Ethyl Ester

The product was obtained by analogy with the method described in Example1.1 and using 3-oxo-pyrrolidine-1-carboxylic acid ethyl ester preparedaccording to Visconti, M et al. Helvetica Chimica Acta 1967, 50 (5)1289-93.

A list of chemical structures and physical data for compounds of theaforementioned formula (I), illustrating the present invention, is givenin tables 1. The compounds have been prepared according to the methodsof the examples.

In the tables, Ph represents a phenyl group, Et represents an ethylgroup; (S), (R) or (Rac.) in the column “Y” indicates thestereochemistry of the carbon atom:

(rac.) means racemic mixture

(R) means absolute R configuration

(S) means absolute S configuration

In table 1, R1 is an unsubstituted pyrimidin-4-yl group or anunsubstituted pyridin-4-yl group, p, o and m represent 2, q represents0. TABLE I (I)

N° R2 Y X R1 R4 R3 n Mp ° C. salt 1 Ph CH(OH) (S) H, H

CO₂Et H 0 169-170 (1:1) (hydrochloride) 2 Ph CO H, H

CO₂Et H 0 227-229 (1:1) (hydrochloride) 3 Ph CH(OH) (S) H, H

CH₃ H 0 271-272 (2:1) (hydrochloride) 4 Ph CO H, H

CH₃ H 0 306-307 (2:1) (hydrochloride) 5 Ph CH(OH) (S) H, H

CO₂Et H 0 118-120 Free base 6 Ph CO H, H

CO₂Et H 0 179-181 Free base 7 Ph CH(OH) (S) H, H

CH₃ H 0 180-182 Free base

In table 2, R1 is an unsubstituted pyridin-4-yl group, p, m represent 2,o represents 1 and q represents 0. TABLE 2 (I)

N° R2 Y X R1 R4 R3 n Mp ° C. salt 1 Ph CH(OH) (S) H, H

CO₂Et H 0 194-195 (1:1) (hydrochloride) 2 Ph CO H, H

CO₂Et H 0 190-191 (1:1) (hydrochloride) 3 Ph CH(OH) (S) H, H

CH₃ H 0 253-254 (2:1) (hydrochloride) 4 Ph CO H, H

CH₃ H 0 231-232 (2:1) (hydrochloride)

Test Example Inhibitory Activity of the Medicament of the PresentInvention Against GSK3β

Two different protocols can be used.

In a first protocol: 7.5 μM of prephosphorylated GS1 peptide and 10 μMATP (containing 300,000 cpm of 33P-ATP) were incubated in 25 mMTris-HCl, pH 7.5, 0.6 mM DTT 6 mM MgCl₂, 0.6 mM EGTA, 0.05 mg/ml BSAbuffer for 1 hour at room temperature in the presence of GSK3beta (totalreaction volume: 100 microliters).

In a second protocol: 4.1 μM of prephosphorylated GSI peptide and 42 μMATP (containing 260,000 cpm 33P-ATP) were incubated in 80 mM Mes-NaOH,pH 6.5, 1 mM Mg acetate, 0.5 mM EGTA, 5 mM 2-mercaptoethanol, 0.02%Tween 20, 10% glycerol buffer for 2 hours at room temperature in thepresence of GSK3beta. Inhibitors were solubilised in DMSO (final solventconcentration in the reaction medium, 1%).

The reaction was stopped with 100 microliters of a solution made of 25 gpolyphosphoric acid (85% P₂O₅), 126 ml 85% H₃PO₄, H₂O to 500 ml and thendiluted to 1:100 before use. An aliquot of the reaction mixture was thentransferred to Whatman P81 cation exchange filters and rinsed with thesolution described above. Incorporated 33P radioactivity was determinedby liquid scintillation spectrometry.

The phosphorylated GS-1 peptide had the following sequence:

NH2-YRRMVPPSPSLSRHSSPHQS(P)EDEE-COOH. (Woodgett, J. R. (1989) AnalyticalBiochemistry 180, 237-241.

The GSK3β inhibitory activity of the compounds of the present inventionare expressed in IC₅₀, and as an illustration the range of IC₅₀'s of thecompounds in table 1 and table 2 is between 1 nanomolar to 1 micromolarconcentrations.

For example compound No. 4 of table 1 shows an IC₅₀ of 0.007 μM andcompound No. 4 of table 2 shows an IC₅₀ of 0.006 μM.

Formulation Example

(1) Tablets

The ingredients below were mixed by an ordinary method and compressed byusing a conventional apparatus. Compound of Example 1  30 mg Crystallinecellulose  60 mg Corn starch 100 mg Lactose 200 mg Magnesium stearate  4mg(2) Soft Capsules

The ingredients below were mixed by an ordinary method and filled insoft capsules. Compound of Example 1 30 mg Olive oil 300 mg  Lecithin 20mg(1) Parenteral Preparations

The ingredients below were mixed by an ordinary method to prepareinjections contained in a 1 ml ampoule. Compound of Example 1 3 mgSodium chloride 4 mg Distilled water for injection 1 ml 

INDUSTRIAL APPLICABILITY

The compounds of the present invention have GSK3β inhibitory activityand are useful as an active ingredient of a medicament for preventiveand/or therapeutic treatment of diseases caused by abnormal activity ofGSK3β and more particularly of neurodegenerative diseases.

1. A dihydrospiro-[cycloalkylamine]-pyrimidone derivative represented byformula (I) or a salt thereof, or a solvate thereof or a hydratethereof:

wherein: X represents two hydrogen atoms, a sulfur atom, an oxygen atomor a C₁₋₂ alkyl group and a hydrogen atom; Y represents a bond, acarbonyl group, a methylene group optionally substituted by one or twogroups chosen from a C₁₋₆ alkyl group, a hydroxyl group, a C₁₋₄ alkoxygroup, a C₁₋₂ perhalogenated alkyl group or an amino group; R1represents a 2, 3 or 4-pyridine ring or a 2, 4 or 5-pyrimidine ring, thering being optionally substituted by a C₁₋₄ alkyl group, a C₁₋₄ alkoxygroup, or a halogen atom; R2 represents a benzene ring or a naphthalenering; the rings being optionally substituted by 1 to 4 substituentsselected from a C₁₋₆ alkyl group, a methylendioxy group, a halogen atom,a C₁₋₂ perhalogenated alkyl group, a C₁₋₃ halogenated alkyl group, ahydroxyl group, a C₁₋₄alkoxy group, a nitro, a cyano, an amino, a C₁₋₅monoalkylamino group or a C₂₋₁₀ dialkylamino group; R3 represents ahydrogen atom, a C₁₋₆ alkyl group or a halogen atom; R4 represents ahydrogen atom, a C₁₋₄ alkoxy carbonyl group, a C₁₋₆ alkyl groupoptionally substituted by 1 to 4 substituents selected from a halogenatom, a hydroxyl group or a C₁₋₄ alkoxy group; o and m represent 1 to 2;n represents 0 to 3; p represents 0 to 2; and q represents 0 to
 2. 2. Adihydrospiro-[cycloalkylamine]-pyrimidone derivative or a salt thereof,or a solvate thereof or a hydrate thereof according to claim 1, whereinR1 represents an unsubstituted 4-pyridinyl group or unsubstituted4-pyrimidinyl group.
 3. A dihydrospiro-[cycloalkylamine]-pyrimidonederivative or a salt thereof, or a solvate thereof or a hydrate thereofaccording to claim 2, wherein R2 represents a benzene ring, the ringbeing optionally substituted 1 to 4 substituents selected from a C₁₋₃alkyl group, a halogen atom, a hydroxyl group or a C₁₋₂ alkoxy group;and R3 represents a hydrogen atom; and R4 represents a C₁₋₄ alkoxycarbonyl group or a C₁₋₃ alkyl group optionally substituted by 1 to 4substituents selected from a halogen atom or a hydroxyl group; and Xrepresents two hydrogen atoms; and Y represents a carbonyl group or amethylene group optionally substituted by a hydroxyl group; and/or prepresents 2 and q represents
 0. 4. Adihydrospiro-[cycloalkylamine]-pyrimidone derivative which is selectedfrom the group consisting of:Ethyl-1′-[(2S)-2-hydroxy-2-phenylethyl]-6′-oxo-8′-(pyridin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylateEthyl-6′-oxo-1′-[2-oxo-2-phenylethyl]-8′-(pyridin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate1′-[(2S)-2-Hydroxy-2-phenylethyl]-1-methyl-8′-(pyridin-4-yl)-3′,4′-dihydrospiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one1-Methyl-1′-(2-oxo-2-phenylethyl)-8′-(pyridin-4-yl)-3′,4′-dihydrospiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-oneEthyl-1′-[(2S)-2-hydroxy-2-phenylethyl]-6′-oxo-8′-(pyrimidin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylateEthyl-6′-oxo-1′-[2-oxo-2-phenylethyl]-8′-(pyrimidin-4-yl)-1′,3′,4′,6′-tetrahydro-1H-spiro[piperidine-4,2′-pyrimido[1,2-a]pyrimidine]-1-carboxylate1′-[(2S)-2-Hydroxy-2-phenylethyl]-1-methyl-8′-(pyrimidin-4-yl)-3′,4′-dihydrospiro[piperidine4,2′-pyrimido[1,2-a]pyrimidin]-6′(1′H)-one,Ethyl1-[(2S)-2-hydroxy-2-phenylethyl]6-oxo-8-(pyridin-4-yl)-1,3,4,6-tetrahydro-1′H-spiro[pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidine]-1′-carboxylateEthyl6-oxo-1-(2-oxo-2-phenylethyl)-8-(pyridin-4-yl)-1,3,4,6-tetrahydro-1′H-spiro[pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidine]-1′-carboxylate1-[(2S)-2-hydroxy-2-phenylethyl]-1′-methyl-8-(pyridin-4-yl)-3,4-dihydrospiro[pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1H)-one1′-Methyl-1-(2-oxo-2-phenylethyl)-8-(pyridin-4-yl)-3,4-dihydrospiro[pyrimido[1,2-a]pyrimidine-2,3′-pyrrolidin]-6(1H)-oneor a salt thereof, or a solvate thereof or a hydrate thereof.
 5. Acompound of formula (III)

wherein R1, R3, R4, m, 0, q and p are as defined for compound of formula(I) according to claim
 1. 6. A medicament comprising as an activeingredient a substance selected from the group consisting ofdihydrospiro-[cycloalkylamine]-pyrimidone derivative represented byformula (I) or salts thereof, or a solvate thereof or a hydrate thereofaccording to claim
 1. 7. A GSK3β inhibitor selected from the group of adihydrospiro-[cycloalkylamine]-pyrimidone derivative represented byformula (I) or salts thereof, or a solvate thereof or a hydrate thereofaccording to claim
 1. 8. Use of a compound according to claims 1 to 4for the preparation of a medicament for preventive and/or therapeutictreatment of a disease caused by abnormal GSK3β activity.
 9. Use of acompound according to claims 1 to 4 for the preparation of a medicamentfor preventive and/or therapeutic treatment of a neurodegenerativedisease.
 10. Use of a compound according to claim 9, wherein theneurodegenerative disease is selected from the group consisting ofAlzheimer's disease, Parkinson's disease, tauopathies, vasculardementia; acute stroke, traumatic injuries; cerebrovascular accidents,brain cord trauma, spinal cord trauma; peripheral neuropathies;retinopathies or glaucoma.
 11. Use of a compound according to claims 1to 4 for the preparation of a medicament for preventive and/ortherapeutic treatment of non-insulin dependent diabetes; obesity; manicdepressive illness; schizophrenia; alopecia; or cancers.
 12. Useaccording to claim 11 wherein cancer is breast cancer, non-small celllung carcinoma, thyroid cancer, T or B-cell leukemia or virus-inducedtumors.